Asthma and allergy affect an estimated 600 million people worldwide and represent an important challenge for basic science to benefit clinical medicine. Our current understanding of these diseases demonstrates that Th2 cells play a major role in the inflammatory responses. However, the factors that induce T cells to differentiate towards a Th2 phenotype remain one of the important unresolved problems in these diseases. There is an established role of IgE in the pathogenesis of asthma and allergic disorders, but antigen-specific IgG is also present in large quantities in the serum of these individuals. We have previously found a novel role for the IgG activating receptor, Fc?RIII, in the regulation of Th2-dependent inflammation in a mouse model. Our findings that previous sensitization, which leads to antigen-specific IgG, could change the response of antigen-presenting cells may provide a new paradigm for therapeutic interventions. Previously, it was believed that antigen-presenting cells in both primary and secondary responses responded similarly stimuli such as TLR agonist. However, our findings now demonstrate that when antigen uptake is mediated by immune complexes instead of simple soluble antigen uptake, the TLR stimulated-DCs produce a differential gene profile that includes the up-regulation of IL-33 cytokine production. Our overall hypothesis is that antigen-specific IgG crosslinking of Fc?R increases Th2-immune responses, in part, through the production of IL-33 by DC. We propose the following specific aims: Aim #1: Determine the role of IL-33 in the augmented Th2 responses produced by immune-complex signaled bone marrow derived DC in vitro and in vivo. In this Aim, we propose to investigate the hypothesis that IL-33 production by BMDCs, directly or indirectly, induces augmented Th2 responses. Aim #2: Determine whether IL-33 is produced by innate immune cells through Fc?R signaling in vivo. In this Aim, we propose to investigate the hypothesis that Fc?R signaling on endogenous TLR4 activated respiratory DCs induces IL-33 production, which in turn augments Th2-mediated inflammation. Our studies will have a significant impact on our understanding of IgG modulation of DC function and how it affects Th2-mediated diseases. Further, we will gain valuable insight into the mechanisms regulating DC-mediated T cell differentiation and have the potential to identify novel targets for therapy in the clinic. In our laboratory, we have the expertise to successfully analyze Th2- mediated airway inflammation in vivo, and all the necessary resources and tools to complete the aims of this proposal. Further, we have made an innovative discovery that DC activation and gene regulation in secondary responses may be influenced by the presence of antigen specific IgG. PUBLIC HEALTH RELEVANCE: Asthma and allergy affect an estimated 600 million people worldwide and represent an important challenge for basic science to benefit clinical medicine. Children are a major and growing population of asthma sufferers. Our studies investigate the mechanisms by which hyper-immune response lead to asthma and allergies.